The First Cell

by Azra Raza

  “So why don’t you find ways to diagnose cancer early also?” my mother asked. She was pleased to hear that devoting my life to understanding and treating MDS was my attempt to do precisely that—catch the leukemia early. “I am glad you are living in America, then. You will have an easier time convincing your colleagues to alter their attitudes. In Pakistan, the systems would be impossible to change in one lifetime.”

  She regularly inquired about my progress in MDS, and when she died less than three months before Harvey in 2002, I sat by her coffin-draped body in the Defense Housing Society Imambarda in Karachi, feeling strangely orphaned in an intellectual sense. I discovered at a deeply experiential level how much strength I had derived from her super-confidence in me, how much I looked forward to our weekly long-distance conversations over the phone, talking about everything under the sun, but especially about my work, which she found fascinating. There was a good reason why we called her the rocket scientist of the family.

  Kis ko ab hoga watan mein aah! mera intezar?

  Kaun mera khat na aanay se rahay ga beqarar?

  —ALLAMA IQBAL

  Now who will wait for me, alas! In my homeland?

  Who will agonize when my letter does not arrive?

  SO WHY DON’T WE FIND WAYS TO DIAGNOSE CANCER EARLY?

  Arrogance. Overconfidence. Contempt.

  These are the words of Robert Weinberg. He is a founding member of the Whitehead Institute for Biomedical Research at MIT, the recipient of the National Medal of Science and the Keio Medical Science Prize. He used these words to describe the attitude of molecular biologists who arrived like knights on white horses to solve the cancer problem through their reductionist approach back in the mid-1970s.

  We were, after all, reductionists, who would parse cancer cells down to their smallest molecular details and develop useful, universally applicable lessons about the mechanisms of cancer development. We would somehow develop logical order out of the phenomenological chaos that the traditional cancer researchers had been accumulating for more than half a century.

  Arrogance like this is never appreciated, and so we tried to keep it under wraps. We were aware of the sensitivities of the ruling barons of cancer research and tried to be non-confrontational. We couched our work in molecular biological terms that were unthreatening for those who had toiled for generations without making much headway into the simple questions of what cancer was and how it began. We knew, all along, that simple answers to complex questions would be greeted with mixed feelings by the large community of more traditional cancer researchers. After all, if we succeeded, we might put many of them out of business.

  I suppose our self-confidence was necessary to make our way through the endless complexity represented by neoplastic disease: We needed to ignore the objections that the old-line cancer researchers repeatedly tossed into our path; they said that cancer was really much too complicated to be understood through simple molecular mechanisms. Indeed, they portrayed our reductionism as simplistic if not simple-minded.

  We have seen that the current cancer landscape is worse than it was in the 1970s. Even today, 95 percent of experimental trials continue to fail. The 5 percent that do succeed extend life of patients by a few months at the cost of millions of dollars. These are roundly touted as paradigm-shifting treatments, game changers. The situation is, both morally and fiscally, profoundly irresponsible. By law, the FDA can only take safety and efficacy data into account when reviewing a drug for approval, not its price tag. On the other hand, Medicare has to cover the cost of a more expensive drug with the same efficacy as a cheaper one if both are FDA approved. My colleague Antonio Fojo, a researcher and oncologist who worked at the National Cancer Institute for three decades, provides a sobering calculation of the cost of health care while reviewing several trials for new cancer treatments:

  In the lung cancer trial, overall survival improved by just 1.2 months on average. The cost for an extra 1.2 months of survival? About $80,000. If we allow a survival advantage of 1.2 months to be worth $80,000, and by extrapolation survival of one year to be valued at $800,000, we would need $440 billion annually—an amount nearly 100 times the budget of the National Cancer Institute—to extend by one year the life of the 550,000 Americans who die of cancer annually. And no one would be cured.

  I had a recent experience underscoring the truth of Robert Weinberg’s criticisms of oncology researchers. I got a call from a young PhD scientist who was preparing to submit an application for an NIH grant. Apparently, he had been studying a gene in animal models, and now it looked like the gene could have a role in abnormal signaling seen in MDS cells. He was preparing a request for a three-year grant. In the first two years, he proposed to examine the role of this gene in a mouse model of MDS. If this showed any relevance, he would like to test human samples. Would I be willing to provide him those samples?

  Of course, I want to help MDS patients in every way I can, which means that I will support any and every researcher interested in studying their disease. I pointed out that I would like to work with him as an equal intellectual partner and collaborator, not as a source who blindly hands over the extremely precious samples. Obviously, I am concerned that the samples I have collected at great financial cost to me and great physical pain to the patient may be squandered on thoughtless experiments by an inexperienced researcher. Further, I would like to decide with him what and how to study the samples. There are absolutely no mouse models or tissue culture cell lines that even remotely recapitulate the human disease. Why spend an enormous amount of resources for two years trying to determine if this gene was important in human MDS by studying absurdly artificial systems? It would make more sense to examine the human tissue first and see whether any follow-up studies were worth pursuing.

  Sadly, several things became clear. The young man had no idea about the human disease MDS, nor did he care to know more about it unless his mouse model showed it could be relevant for his research. I offered to meet so we could discuss what is important for MDS patients and determine how his research interests could align with those patient needs. He again politely refused. All he wanted was an official letter of support from me that could be clipped to his grant application attesting to the fact that he would have access to human samples in year three of his grant. Most grant applications follow the same trajectory, leading to an enormous waste of resources.

  After a few decades of accumulating strangeness in the field, we have come to a point when there is little connection between where we started and where we have arrived. To change a situation, one has to first lift the blinders and dare to see the situation for what it is. By trying to fit an impossibly complex problem into a straightforward, simplistic, linear narrative, cancer research has reached a new reductio ad absurdum milestone. There is a crisis in the field. The bizarreness of things we are doing both in clinical and basic science research is effectively cloaked under important-sounding terms, conveying a reassuring sense of objectivity—best practices, evidence-based medicine, precision oncology, genetically engineered mice. Mostly we have euphemisms to sweeten the bitter truth that we don’t really have better treatments than what we were offering fifty years ago.

  In 1980, I was briefly at George Washington University and frequently had lunch with Dr. Ayub Ommaya, the great Pakistani neurosurgeon who invented the Ommaya reservoir for delivering drugs into the brain. He was obsessed with everything to do with the brain. I once asked him what he thought would be the final level of reductionism needed to sight the root of consciousness. “Azra, taking apart the Taj Mahal brick by brick to discover the source of its beauty will yield only rubble. It is the same with the brain. The emergent complexity from simple individual parts accounts for its essential mystery.” It is also the reason why cancer will not yield its secrets through a reductionist approach.

  Cancer, when it appears, is sudden. And yet it is also the result of a gradual accumulation of small changes, intricately tied to aging. Each perhaps is inconseq
uential by itself, but each contributes toward the eventual instability of the system. I talked about a growing pile of sand and how the concept of critical states explains the way a single grain can set off an avalanche. In a similar manner, the biologic disturbances bubbling under the surface in an aging body tip the system toward entropy in a slow, unrelenting manner, such that cancer can arise suddenly from what, in other circumstances, would be an inconsequential event. Self-organized criticality develops both inside the cell and in its microenvironment with age. Reductionism calls for finding the “cancer gene.” But what tips a system into cancer isn’t necessarily a particular mutation but the last mutation that causes the avalanche, a catastrophic phase-transition into cancer. That mutation may be no different in lethality from thousands of others, which the cell’s DNA sustained over the years. Similarly, the one senescent cell whose appearance tips the garbage-collecting system, causing the soil to become pro-inflammatory, too toxic for healthier cells, is no different from the million others before it. With age, the entire system, the seed and the soil, like a growing pile of sand, becomes more and more prone to unpredictable, abrupt collapses. The question should really be why cancer does not occur in every old person. The answer is because juxtaposition of the immortalized mutated seed with the appropriately poisoned soil, the perfect “fitness landscape,” happens rarely.

  Cancer and aging are two sides of the same coin. Understanding one, in all its granularity, can automatically reveal the secrets of the other. This is how complex cancer is. It is pure arrogance to think the problem can be solved by a few molecular biologists if they put their minds to it. Cancer is a perfidious, treacherous, evolving, shifting, moving target, far too impenetrable to be deconstructed systematically, far too dense to lend itself in all its plurality to recapitulation in lab dishes or animals.

  MDS CAN BE a deadly disease by itself without necessarily transforming to leukemia. I became interested in identifying individuals at risk of developing this preleukemic condition, a pre-MDS state. In fact, we do know of at least one such high-risk group—patients previously treated with chemoradiation therapy for other cancers have a very small (1–2 percent) chance of developing MDS, sometimes many years after having received the toxic agents. My idea was to identify MDS-susceptible individuals by monitoring cancer survivors through twice-yearly “liquid biopsies” and look for the appearance of markers associated with MDS. In 1998, I began to obtain blood samples from patients treated previously for breast, prostate, lung, and GI cancers and lymphomas. We collected and stored hundreds of samples along with accompanying clinical information on these patients in the tissue repository. I applied for a grant, formally starting the TIME Center (Therapy Induced Malignancy Evaluation), and received incredibly generous support from the Women’s Board of Rush University.

  After Harvey died and I moved out of Chicago, I was able to transfer the entire tissue repository with me. However, as the accompanying research charts of patients were being loaded on the moving truck, despite having all the requisite permissions of the institutional review board, hospital lawyers, and a hundred administrators, an uninvolved nurse supervisor arrived on the scene and decided to take matters into her own hands. She informed my program directors, Dr. Naomi Galili and Laurie Lisak, PA, supervising the move that some of the research charts looked thicker than actual patient charts from which they were copied so she could not let them leave the university premises until she made sure that every chart was an exact duplicate. The majority of them were the charts of the TIME Center patients. Of course, there was an obvious reason for this discrepancy. Because of the chaos following Harvey’s prolonged illness and death, we had not yet computerized the research charts, and all the research data were also present in those actual physical hard copies along with the duplicated clinical records. She was not willing to listen to any explanation and directed the movers to unload hundreds of research files, promising prompt release once she had cleared her confusion. Needless to say, despite trying for years, I have been unable to overcome the institutional red tape. It was always about the two institutions involved in legal issues of intellectual property rights and data ownership. Long letters of appeal not just to the chair of the IRB and chair of medicine at the university but even to the FDA to intervene have been in vain. As a result of the university’s recalcitrance, the TIME Center charts are rotting in a warehouse in Chicago and the samples in my freezers at Columbia. We can do nothing with the samples without the accompanying clinical information.

  While I have been unable to make use of these precious TIME Center samples, I was delighted to see a study led by Pinkal Desai, who found somatic mutations in blood samples obtained as part of the Women’s Health Initiative, sometimes years before the appearance of acute myeloid leukemia in some of these individuals. This study validates my concept of the TIME Center inaugurated two decades ago. It is critical to study our TIME Center samples today because many of those individuals must have developed MDS by now, and we are missing a golden opportunity to understand what is unique about them. It is also the type of biomarker information needed to design strategies for detecting the first cell. But once more, bureaucracy became, as James Boran pointed out, the glue that greased the wheels of progress. A system has evolved geared more toward protecting institutions and less toward protecting patients. Another example of this is the “Informed Consent Form” for experimental trials. Nowadays, these can run up to dozens of pages and contain paragraph after paragraph of confusing, cut-and-paste language, demanded by the NIH, FDA, IRB, and trial sponsors, which has little relevance for the patient. Most patients look baffled when presented with these forms. By law, we also have to insist that they read every word of the document before signing. One of my patients threw up his arms in utter desperation. “Dr. Raza, first I need to hire a lawyer to explain this to me!”

  BECAUSE I HAVE been speaking and writing about cancer and its discontents for years, I am familiar with the common misunderstandings that arise in the minds of my audience. I am not saying that all scientific research on animal models should be abandoned. What I am saying is that animal models are misleading and harmful for cancer drug development, because the disease cannot be reproduced in such simplistic, artificial systems. I am not saying that all cancer research should stop except that related to early detection. What I am saying is that more resources have to be dedicated to this area. I am not saying that technologies like CRISPR are all hype. What I am saying is that the discovery of CRISPR as a tool in molecular biology is truly revolutionary, but its application in fixing human cancer cells by cutting and pasting DNA needs years of careful study before commercializing it into billion-dollar companies. I am not saying that advances in cancer treatment are entirely absent. What I am saying is that they are too few, occurring in an incremental manner, not curative, extend survival by months at best, and at this rate will take too long to make a substantial difference in decades to come. I am not saying that immune therapies, especially CAR-T cell therapies, are universally overrated, empty promises. What I am saying is that so far, they have only benefited a subset of highly select patients. They are a long way from becoming the routine in clinic because of their dreadful physical, psychological, emotional, and financial toxicities, as well as the lack of suitable, specific target identification. I am not saying that cancer researchers are insincere and driven only by personal greed. Of course mostly everyone is sincere and has good intentions. What I am saying is that the cancer paradigm has reached a grotesque, unrecognizable, destabilized end point. The entire society needs to pause, think deeply about the overall complexity of our challenge, and admit that presently, we lack even the conceptual archetypes for solving so dense a problem. The public needs to demand that more of their tax dollars support researchers developing strategies for early detection of cancer that don’t require detailed, intricate understanding of every molecular signaling pathway in a cancer cell.

  I COULD NOT have written this book when I was thirty yea
rs old. After being in this field for all of my adult life, I am even more invested in demanding a complete overhaul of the current cancer culture that has evolved. I know that mine is a small, relatively lonely voice in the field, but I refuse to be silenced. I received a lesson in the power of individual engagement quite early on in my career. An international conference was organized in the United States, to which, despite strong opposition and threats of a boycott, researchers and oncologists from an apartheid-ridden South Africa were invited. The protesters were warned not to make a brouhaha, because there is no politics in medicine, cancer is a universal issue, and the platform being provided to the presenters was critical for precisely this reason—racially diverse cancer patients could be compared in an international setting. Tensions were high in the cavernous hall where the white South African team presented their data showing that the incidence of esophageal cancer in the Bantu natives was higher than that in the white population. At the end of the presentation, there was total silence until one young African American oncologist raised his hand, stood up, and calmly asked in a loud, controlled, powerful voice, “Dr. Johnson, do you think that the incidence of esophageal cancer in the Bantu natives is high because of swallowed pride?”

  There is no activism without despair, no despair without hope. Despair can be as powerful an engine for change as hope. In the cases of Omar and Andrew, there was no best decision. The question for them was not what to choose but how to achieve a balance between hope and despair. Once it became known that the primary tumors were not removed in their entirety, their choices were to die of the cancer or of the treatment. Which was less painful? False hope and positive narratives are not the answer. Barbara Ehrenreich in a telling passage writes about her diagnosis of breast cancer: “The trick, as my teen hero Camus wrote, is to draw strength from the ‘refusal to hope, and the unyielding evidence of a life without consolation.’ To be hope-free is to acknowledge the lion in the tall grass, the tumor in the CAT scan, and to plan one’s moves accordingly.”